Myelofibrosis (“MF”) is a rare disease mainly affecting people of older age. MF is a BCR-ABL1-negative myeloproliferative neoplasm (“MPN”) that presents de novo (primary) or may be preceded by polycythemia vera (“PV”) or essential thrombocythemia (“ET”). Clinical features include progressive anemia, marked splenomegaly, constitutional symptoms (e.g. fatigue, night sweats, bone pain, pruritus, and cough) and weight loss (Tefferi A, N Engl J Med 342:1255-1265, 2000). Median survival ranges from less than 2 years to over 15 years based on currently identified prognostic factors (Cervantes F et al., Blood 113:2895-2901, 2009; Hussein K et al. Blood 115:496-499, 2010; Patnaik M M et al., Eur J Haematol 84:105-108, 2010). Mutations involving JAK2 (James C et al., Nature 434:1144-1148, 2005; Scott L M et al., N Engl J Med 356:459-468, 2007), MPL (Pikman Y et al., PLoS Med 3:e270, 2006), TET2 (Delhommeau F et al., N Engl J Med 360:2289-2301, 2009), ASXLI (Carbuccia N et al., Leukemia 23:2183-2186, 2009), IDH1/IDH2 (Green A et al., N Engl J Med 362:369-370, 2010; Tefferi A et al., Leukemia 24:1302-1309, 2010), CBL (Grand F H et al., Blood 113:6182-6192, 2009), IKZF1 (Jagcr R et al., Leukemia 24:1290-1298, 2010), LNK (Oh S T et al., Blood 116:988-992, 2010), or EZH2 (Ernst T et al., Nat Genet. 42:722-726) have been described in patients with MPN, including those with MF. Some mutations occur at high frequency in MF (e.g. JAK2 mutations in ˜50% patients), and either directly (e.g. JAK2 or MPL mutations) or indirectly (e.g. LNK or CBL mutations) induce JAK-STAT hyperactivation.
The currently available treatments are not effective in reversing the process of MF, be it primary or secondary disease. The only potential for cure of the disease to date is bone marrow transplantation. However, most patients are not suitable bone marrow transplant candidates because of the older median age at diagnosis, in which transplant-related morbidity and mortality tends to be high. Thus management options of MF are currently inadequate to meet the needs of all patients. The main options for active intervention include cyto-reductive therapy, e.g. with hydroxyurea, treatment of anemia with androgens, erythropoietin and splenectomy. These options have not been shown to improve survival and are largely seen as palliative (Cervantes F., Myelofibrosis: Biology and treatment options, European Journal of Haematology, 2007, 79 (suppl. 68) 13-17). Therefore, there is a need to provide additional therapy options for MF patients.